2-Aminonitriles of the formula: ##STR1## or 2-aminoamides of the formula: ##STR2## where A is not equal to B contain an asymmetric center at the C-2 or alpha (a) carbon atom. The presence of an asymmetric center results in two molecules, which are enantiomers, or mirror images of each other. Each enantiomer is optically active: one rotates plane polarized light to the right and is termed dextrorotatory (d or +) and the other enantiomer rotates plane polarized light to the left and is termed levorotatory (1 or -). Rotation of plane polarized light by enantiomers is to an equal degree but in opposite directions. The enantiomers by convention are designated D and L (relative configuration) and/or S and R (absolute configuration). See E. L. Eliel, Stereochemistry of Carbon Compounds. McGraw-Hill, 1962, p. 88. When an equal number of d and 1 enantiomeric molecules exist together, a racemic (optically inactive) mixture results. When an unequal number of d and 1 enantiomeric molecules exist together an optically impure mixture results.
Formulas I and II above as well as formulas III and V below do not designate a particular stereochemical configuration. Therefore, they may represent an enantiomer, its mirror image, a racemic form, or an optically impure form, in which the enantiomers are not present in equal numbers.
It is well known that when a biologically active compound contains a center of a symmetry which produces two enantiomers, one of the enantiomers often possesses most or all of the biological activity. In such cases the other enantiomer is biologically inactive, and is therefore an impurity. Examples are sugars (D-glucose), amino acids (phenylglycine and phenylalanine), LSD, and the prostaglandins. Therefore, it is highly advantageous from a pharmaceutical point of view to obtain the biologically active enantiomer in an optically pure form from an optically impure or racemic mixture.
The hydrolysis of 2-aminonitriles to the corresponding 2-aminoacids (a-aminoacids) is well known. The hydrolysis of amides such as those of formula II to the corresponding acid is also well known to those skilled in the art. Since the hydrolysis does not involve reaction at the asymmetric center no change in relative or absolute configuration takes place during the hydrolysis reaction. Therefore, if one starts with an optically active 2-aminonitrile one obtains the corresponding optically active 2-aminoacid. Likewise, if one starts with a racemic 2-aminonitrile one obtains a racemic 2-aminoacid. See for example Gr. Brit. Pat. No. 1,382,688; Basic Principles of Organic Chemistry, J. D. Roberts and M. C. Caserio, W. A. Benjamin, Inc., N. Y., 1964, page 706; Advanced Organic Chemistry Reactions Mechanisms and Structure, J. March, McGraw-Hill, 1968, p. 660; U.S. Pat. No. 3,890,379 and J. Schawartz et al., Chem. Ind. 1698 (1968).
The biological activity of the 2-aminoacids usually resides with only one of the enantiomers. The optically active 2-aminoacids are commercially important for the production of various antibiotics, in particular cephalosporins and penicillins as is well known to those skilled in the art. The optically active 2-aminoacids are also useful in resolution of optically impure compounds as is also well known to those skilled in the art. Since the 2-aminoacids are usually obtained by hydrolysis of the corresponding 2-aminonitrile or 2-aminoamide it would be highly desirable to be able to obtain the desired 2-aminonitrile or 2-aminoamide in optically pure form prior to the hydrolysis reaction.
Methods of resolving racemic mixtures into their optically pure enantiomers are well known to those skilled in the art. See for example, Roberts and Caserio, supra, page 497; March, supra, page 92, and Eliel, supra, pages 47-85. Perhaps the most general resolution procedure is to form diastereomers from the enantiomers. In the case of 2-aminonitriles or 2-aminoamides this is best done by salt formation with an optically active acid and then recovery of one of the diastereomers by fractional crystallization. The recovered diastereomer is then neutralized to obtain the optically pure enantiomer.
With regard to 2-aminonitriles, H. Reihlen, E. Weinbrenner, and G. v Hessling, Ann. 534,247 (1938) reported the resolution (low yield) of racemic 2-aminophenylacetonitrile using optically active tartaric acid.
Since a racemic mixture contains equal numbers of the D and L enantiomers, resolution of a racemic mixture provides 50% of the total amount of the compound present in optically pure form, i.e., one of the enantiomers. Until 1974 a 50% yield of an optically pure enantiomer from a racemic mixture of 2-aminonitriles was considered optimal. U.S. Pat. No. 3,941,796 discloses a one-step method for resolution with racemization of .alpha.-amino-.epsilon.-caprolactams so as to obtain yields of greater than 50% of the desired enantiomer. The process utilizes a strong base, a metal ion, a derivative of a chelating carbonyl compound and seed crystals. The present invention not only does not require a strong base, a metal ion or seed crystals but does not require that the carbonyl compound (aldehyde or ketone) be a chelating agent.
U.S. Pat. No. 3,808,254 discloses the use of alkanoic acids to improve the resolution of .alpha.-aminophenylacetonitrile using optically active tartaric acid. This is the first published report which describes obtaining yields greater than 50% of one enantiomer from a racemic mixture. U.S. Pat. No. 3,808,254 further discloses a reaction time for resolution of 2-aminophenylacetonitrile ". . . ranging from about 4 hours to about 72 hours, preferably about 8 to about 15 hours." The actual times disclosed by examples 1 thru 9 of U.S. Pat. No. 3,808,254 are "overnight", "one day", "a day", and "several days". The method of the present invention for obtaining optically pure 2-aminonitriles and 2-aminoamides does not use alkanoic acids and has the surprising and unexpected result of obtaining optically pure 2-aminoarylacetonitriles in amounts greater than originally present in 1 hour or less. From a commercial point of view this is a distinct advantage over prior processes.
Gr. Brit. Pat. No. 1,423,822 dicloses a process for resolution of amino acid esters by use of optically active tartaric acid and an aldehyde or ketone. The process of Great Britain Pat. No. 1,423,822 differs from the process of the present invention in that the process of Great Britain Pat. No. 1,423,822 is a process for resolving a racemic mixture of .alpha.-aminoacid esters whereas the present process is a process for producing optically pure 2-aminonitriles and 2-aminoamides. Both processes use optically active acids and aldehydes or ketones. The present invention has a surprising and unexpected result of having much shorter reaction times. For example, even though Great Britain Pat. No. 1,423,822 states that reaction times of 20-24 hours is usual and can be as low as 6-8 hours, the examples set forth in Great Britain Pat. No. 1,423,822 disclose much longer times. For instance, in Example 1 the solution was stirred for 5 days. In Table A the reaction times for use of aldehydes in the resolution process are from 18- 70 hours. Using ketones for the resolution process the reaction times are 44-288 hours, see Table B.